The project involves the structure determination by single crystal X-ray diffraction of both natural and synthetic anticancer agents. In each group of compounds specific plans are described for the interpretation of the results and for the correlation of the observations with the activity of the compounds. In a continuing project the structures of new natural products isolated from marine organisms will be determined. This will involve all pure compounds with very high activity (O.O1 mug/ml) as well as those new compounds which are based on a novel chemical skeleton. In general also the absolute configuration of the compounds will be determined. The most active compounds have M.W. above 1000 and can be peptides, alkaloids, macrolides or polyethers and sometimes have a combination of these characteristics. Additionally a special effort will be made to understand all conformational characteristics of didemnin for which we recently determined the structure. This will be done by structure determination of others in the same family, various crystal forms and by molecular dynamics simulations. The structures of a series of heteroarotinoids will be determined. These synthetic analogs will explore different chemical features of the compounds. The selection will be made on the basis of their activity with respect to the inhibition of ODC production. It is hypothesized that the compounds are inhibitors for protein kinase C. The crystal structures of all compounds more active than retinoic acid and structurally related less active compounds will be determined. The conformations of the compounds will be explored with molecular mechanics. The structures of a set of compounds with pure antiestrogenic activity will be determined. These compounds are cyclopropyl analogs of diphenyl and triphenyl ethylene derivatives and based on the newly synthesized diphenyl gen dichloro cyclopropane (Analog II) which has been shown to have only antiestrogenic activity. The structures present in the literature and our own results will be used to understand their molecular function in binding the estrogen receptor or more generally those structural features of the molecules which result in pure antagonist action.